Urticaria pathophysiology
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Anahita Deylamsalehi, M.D.[2]
Overview
There are numerous mechanisms hypothesized to be responsible in pathogenesis of urticaria. One of the prominent urticaria pathogenesis seems to be inflammatory processes due to increased immune cells activity. Basophils, mast cells, macrophages, neutrophils and T cells are some of the most common immune cells known to be responsible in pathogenesis of urticaria. Among them, basophils and mast cells have more eminent role in urticaria development and their activation has been related to some intracellular signal defect and/or autoimmune disorders. Some immunoglobins, such as IgE have been detected in patients suffering from urticaria. For instance , IgE anti-IL-24 is one of these IgE autoantigens that have been found in all patients with chronic spontaneous urticaria. Moreover, complement system is also responsible in pathogenesis of chronic spontaneous urticaria and role of some complements, such as C3, C4 and C5 have been established. Based on numerous studies, urticaria patients may have some genetical changes. Upregulation of 506 genes and downregulation of 51 genes have been reported in the affected skin with chronic spontaneous urticaria. Most of the upregulated genes were involve in adhesion (such as SELE (1q24)), cell activation (such as CD69), and chemotaxis (such as CCL2). It is crystal clear that urticaria is associated with autoimmune diseases such as hashimoto's thyroiditis. Other associations are mastocytisis such as urticaria pigmentosa, atopic diseases such as atopic dermatitis, hay fever and allergic asthma and Systemic lupus erythematosus and angioedema.
Pathophysiology
Wheal formation pathogenesis
There are some factors responsible in pathogenesis of wheals:[1]
- There are some endogenous anti-angiogenic mediators, which are degraded from extracellular matrix components such as endostatin (ES) and thrombospondin-1 (TSP-1). These mediators regulate functional activity of vascular endothelial growth factor (VEGF).
- Endostatin (ES) and thrombospondin-1 (TSP-1) levels are elevated in patients with urticaria. Apart from their anti-angiogenic effects, they are responsible for destabilizing the endothelial cells contact, which leads to formation of wheals, the famous dermatologic presentation of urticaria.
- NO synthesis is one of the responses to endostatin (ES) which can also acts as a vasoactive mediator. The consequent vasodilation eventually leads to wheals formation through vascular leakage.
Acute urticaria
- The pathophysiology of acute urticaria is production of specific IgE against food protein antigens.[2]
- Viral infection is the most common cause of acute urticaria, mainly upper respiratory tract infections.[3]
Chronic spontaneous urticaria
There are numerous mechanisms hypothesized to be responsible in pathogenesis of chronic spontaneous urticaria:[4][5][6][7][8][9][10][11][12][13][14][15][16]
- Inflammation has been known as a responsible factor in the pathogenesis of urticaria, especially in chronic spontaneous urticaria.
- One of the findings that supports the role of inflammation in the urticaria pathogenesis is IL-31. This interleukin is primarily produced by activated Th2 lymphocytes and mast cells, as well as a skin-homing T cell (CD45R0 CLA+T cell) and plays a cardinal role in chronic skin inflammation.
- An imbalance in some anti-inflammatory adipokines (such as adiponectin) and proinflammatory adipokines (such as lipocalin-2 (LCN2)) has been found in chronic urticaria.
- Matrix metallopeptidases (MMPs) are elevated in patients with chronic spontaneous urticaria. MMPs are responsible in the inflammation process as shown below:
Macrophages, neutrophils, T cells, and mast cells → MMP-9 → Cleavage of pro-inflammatory chemokines/cytokines → Migration and activation of more immune cells
- Activation of mast cells and basophils has been increased in urticaria.[17] There are two known mechanisms that lead to mast cell and basophil activation in the process of urticaria:
1)Defect in intracellular signaling: Improper activation of spleen tyrosine kinase (Syk) or improper inhibition of Src homology 2 (SH2)-containing inositol phosphatases (SHIP).
2)Autoimmune mechanisms: Antibody-mediated mast cell and basophil activation via IgG or IgE mediated pathways.- At least 200 IgE autoantigens (soluble or membrane-bound), were recently found in patients with chronic spontaneous urticaria. IgE anti-IL-24 is one of these IgE autoantigens that have been found in all patients with chronic spontaneous urticaria.
- Approximately, 35%–40% of patients have IgG anti-FcεRIα (an α subunit of the high affinity IgE receptor).
- A basophilic abnormality has been seen in a number of patients with chronic spontaneous urticaria. Elevated levels of phosphatases, such as Src homology tyrosine phosphatase-1 (SHP-1), have been detected in the defective basophils.[18]
- Complement system is also responsible in pathogenesis of chronic spontaneous urticaria.
- In-vitro experiments have been demonstrated the role of C5a in enhancement of IgG-dependent histamine release from basophils and mast cells in chronic urticaria.[5]
- In a study done on 70 patients with chronic spontaneous urticaria significant elevated levels of C3 and C4 have been detected, compared to the normal population.
- Increased production of C3 and C4 by liver is probably due to elevation in pro-inflammatory cytokines, such as IL-1β, IL-6 or tumor necrosis factor (TNF). C3a itself further stimulates the secretion of other pro-inflammatory cytokines and chemokines and expresses on cells responsible in urticaria formation, such as mast cells, basophils, eosinophils, neutrophils and monocytes. Anaphylatoxin C3a is also able to stimulate histamine release which is capable of causing vasodilatation and consequent increased [[permeability of small blood vessels.
- Increased expression of tissue factor by activated eosinophils first activates extrinsic coagulation pathway and then the intrinsic coagulation pathway and consequent generation of thrombin has been reported.
- Tumor necrosis factor alpha (TNF-alpha) produced by dermal mast cells has been detected at the site of urticaria lesions.
- The following table is a summary of some elevated mediators in chronic urticaria.[17][19][20]
| Mediator | Effects |
|---|---|
| Histamine | Vasodilatation, increased vascular permeability |
| LTC4 | Similar to histamine |
| LTB4 | Potentiate vasodilatation, increased vascular permeability, and smooth muscle contraction |
| PGD2 | Chemotaxis for both neutrophils and eosinophils |
| Tumor necrosis factor-alpha | hyperexpression of adhesion molecules on endothelial cells, chemotaxis for neutrophils and boost leukocyte rolling and adhesion |
| Interleukin-1 | Proinflammation, mast cells and lymphocyte actication |
| Interleukin-4 | Chemotaxis for both neutrophils and eosinophils |
| Interleukin-5 | Chemotaxis for eosinophils |
| Interleukin-6 | Lymphocyte actication, proinflammation |
| Interleukin-8/CXCL2 | Neutrophils chemotaxis, degranulation, respiratory burst and adhesion to endothelial cells. |
| MCP-1/CCL2 | Chemotaxis for eosinophils |
| MIP-1 alpha/CCL3 | Chemotaxis for eosinophils |
| Interleukin-16 | Chemotaxis for T cell |
| RANTES/CCL5 | Chemotaxis for eosinophils |
Non-Allergic Urticaria
Mechanisms other than allergen-antibody interactions are known to cause histamine release from mast cells. Many drugs, such as morphine, can induce direct histamine release not involving any immunoglobulin molecule. Also a diverse group of signaling substances called neuropeptides have been found to be involved in emotionally induced urticaria. Dominantly inherited cutaneous and neurocutaneous porphyrias (porphyria cutanea tarda, hereditary coproporphyria, variegate porphyria and erythropoietic protoporphyria) have been associated with solar urticaria. The occurrence of drug-induced solar urticaria may be associated with porphyrias.
Genetics
- In one study upregulation of 506 genes and downregulation of 51 genes have been reported in the affected skin with chronic spontaneous urticaria. Most of the upregulated genes were involve in adhesion (such as SELE (1q24)), cell activation (such as CD69), and chemotaxis (such as CCL2).[21]
- CIAS1 gene mutation has been linked to cryopyrin-associated periodic syndrome (CAPS) a neonatal-onset multisystem inflammatory disorder (NOMID) which presents with urticaria.[2]
- The following table is a summary of genes that have been significantly associated with some phenotypes of urticaria and list of countries which the studies have been done in the,: [22]
Abbreviations: AICU: aspirin-intolerant chronic urticaria; AIU: aspirin-intolerant urticaria; CU: chronic urticaria;
| Genes | Associated phenotype | Country |
|---|---|---|
| FcεRIα | AICU | Korea |
| FcεRIβ | AICU | Korea |
| FcεRIγ | AICU | Korea |
| HNMT | AICU | Korea |
| TNF-α | AIU | Korea |
| TGF-β1 | CU, AICU | Iran |
| ADORA3 | AIU | Korea |
| IL-10 | AIU | Korea |
| ALOX5 | AIU | Korea |
| CYSLTR1 | AICU | Korea |
| LTC4S | AIU | Poland, Venezuela |
| PTGER4 | AICU | Korea |
| CYP2C9 | AIU | Korea |
| ACE | CU with angioedema | Turkey |
| PTPN22 | CU | Poland |
Associated Conditions
- Autoimmune disease: Presence of autoimmune conditions, such as autoimmune thyroid disease has been found in a fraction of patients with urticaria. Moreover, some studies detected IgE and IgG anti-TPO antibodies in some patients with chronic spontaneous urticaria. These antibodies might be responsible for mast cells and basophils degranulation.[23][24][25][26][27]
- Elevated antithyroid antibodies, such as IgG antithyroglobulin, immunoglobulin E (IgE) antithyroperioxidase and immunoglobulin G (IgG) antithyroperioxidase, have been detected in patients with chronic spontaneous urticaria.
- Hashimoto's thyroiditis has been detected in a sub-population of patients with chronic spontaneous urticaria.
- Mastocytisis such as urticaria pigmentosa
- Atopic disease
- There are some reports on urticaria presentation in 50% of patients who suffer from atopic dermatitis, hay fever and allergic asthma.[3]
- Another study done on children with atopic dermatitis delineated that approximately 16% of them developed urticaria within a 18 months surveillance.[28]
- Systemic lupus erythematosus[12]
- Concurrent angioedema has been seen in 40% of patients who suffer from chronic urticaria.[22]
- Patients with urticaria have higher chance of hypertension development.[4]
- Higher chance of urticaria is reported among patients with metabolic syndrome, compared to the normal population.[29]
Microscopic Pathology
The following changes have been found in microscopic evaluation of urticaria:[4][30][21][3]
- Angiogenesis
- Vascular formation has been detected in urticaria biopsies, especially in chronic urticaria.
- Elevation in some pro-angiogenic mediators, such as VEGF, has been directly linked with formation of new blood vessels in the skin of chronic spontaneous urticaria patients.
- High concentration of inflammatory cells (predominantly mononuclear cells) per high-powered field.
- Increased endothelial adhesion molecules
- Microscopic evaluation of delayed pressure urticaria demonstrated inflammatory mediatorrs in the mid‐ to lower dermis.
References
- ↑ Isenberg JS, Ridnour LA, Dimitry J, Frazier WA, Wink DA, Roberts DD (2006). "CD47 is necessary for inhibition of nitric oxide-stimulated vascular cell responses by thrombospondin-1". J Biol Chem. 281 (36): 26069–80. doi:10.1074/jbc.M605040200. PMID 16835222.
- ↑ 2.0 2.1 Deacock SJ (2008). "An approach to the patient with urticaria". Clin Exp Immunol. 153 (2): 151–61. doi:10.1111/j.1365-2249.2008.03693.x. PMC 2492902. PMID 18713139.
- ↑ 3.0 3.1 3.2 Zuberbier T (2003). "Urticaria". Allergy. 58 (12): 1224–34. doi:10.1046/j.1398-9995.2003.00327.x. PMID 14616095.
- ↑ 4.0 4.1 4.2 Puxeddu I, Petrelli F, Angelotti F, Croia C, Migliorini P (2019). "Biomarkers In Chronic Spontaneous Urticaria: Current Targets And Clinical Implications". J Asthma Allergy. 12: 285–295. doi:10.2147/JAA.S184986. PMC 6759208 Check
|pmc=value (help). PMID 31571935. - ↑ 5.0 5.1 Kikuchi Y, Kaplan AP (2002). "A role for C5a in augmenting IgG-dependent histamine release from basophils in chronic urticaria". J Allergy Clin Immunol. 109 (1): 114–8. doi:10.1067/mai.2002.120954. PMID 11799375.
- ↑ Schmetzer O, Lakin E, Topal FA, Preusse P, Freier D, Church MK; et al. (2018). "IL-24 is a common and specific autoantigen of IgE in patients with chronic spontaneous urticaria". J Allergy Clin Immunol. 142 (3): 876–882. doi:10.1016/j.jaci.2017.10.035. PMID 29208545.
- ↑ Schmoldt A, Benthe HF, Haberland G (1975). "Digitoxin metabolism by rat liver microsomes". Biochem Pharmacol. 24 (17): 1639–41. PMID doi.org/10.1186/1476-9255-10-22 Check
|pmid=value (help). - ↑ Ritchie RF, Palomaki GE, Neveux LM, Navolotskaia O (2004). "Reference distributions for complement proteins C3 and C4: a comparison of a large cohort to the world's literature". J Clin Lab Anal. 18 (1): 9–13. doi:10.1002/jcla.10095. PMC 6808116 Check
|pmc=value (help). PMID 14730551. - ↑ Walsh LJ, Trinchieri G, Waldorf HA, Whitaker D, Murphy GF (1991). "Human dermal mast cells contain and release tumor necrosis factor alpha, which induces endothelial leukocyte adhesion molecule 1". Proc Natl Acad Sci U S A. 88 (10): 4220–4. doi:10.1073/pnas.88.10.4220. PMC 51630. PMID 1709737.
- ↑ Raap U, Wieczorek D, Gehring M, Pauls I, Ständer S, Kapp A; et al. (2010). "Increased levels of serum IL-31 in chronic spontaneous urticaria". Exp Dermatol. 19 (5): 464–6. doi:10.1111/j.1600-0625.2010.01067.x. PMID 20163453.
- ↑ Trinh HK, Pham DL, Ban GY, Lee HY, Park HS, Ye YM (2016). "Altered Systemic Adipokines in Patients with Chronic Urticaria". Int Arch Allergy Immunol. 171 (2): 102–110. doi:10.1159/000452626. PMID 27902979.
- ↑ 12.0 12.1 Kolkhir P, Pogorelov D, Olisova O, Maurer M (2016). "Comorbidity and pathogenic links of chronic spontaneous urticaria and systemic lupus erythematosus--a systematic review". Clin Exp Allergy. 46 (2): 275–87. doi:10.1111/cea.12673. PMID 26545308.
- ↑ Kessel A, Bishara R, Amital A, Bamberger E, Sabo E, Grushko G; et al. (2005). "Increased plasma levels of matrix metalloproteinase-9 are associated with the severity of chronic urticaria". Clin Exp Allergy. 35 (2): 221–5. doi:10.1111/j.1365-2222.2005.02168.x. PMID 15725195.
- ↑ Asero R, Tedeschi A, Marzano AV, Cugno M (2017). "Chronic urticaria: a focus on pathogenesis". F1000Res. 6: 1095. doi:10.12688/f1000research.11546.1. PMC 5506533. PMID 28751972.
- ↑ Cugno M, Marzano AV, Tedeschi A, Fanoni D, Venegoni L, Asero R (2009). "Expression of tissue factor by eosinophils in patients with chronic urticaria". Int Arch Allergy Immunol. 148 (2): 170–4. doi:10.1159/000155748. PMID 18802362.
- ↑ Godse K, De A, Zawar V, Shah B, Girdhar M, Rajagopalan M; et al. (2018). "Consensus Statement for the Diagnosis and Treatment of Urticaria: A 2017 Update". Indian J Dermatol. 63 (1): 2–15. doi:10.4103/ijd.IJD_308_17. PMC 5838750. PMID 29527019.
- ↑ 17.0 17.1 Jain S (2014). "Pathogenesis of chronic urticaria: an overview". Dermatol Res Pract. 2014: 674709. doi:10.1155/2014/674709. PMC 4120476. PMID 25120565.
- ↑ Vonakis BM, Vasagar K, Gibbons SP, Gober L, Sterba PM, Chang H; et al. (2007). "Basophil FcepsilonRI histamine release parallels expression of Src-homology 2-containing inositol phosphatases in chronic idiopathic urticaria". J Allergy Clin Immunol. 119 (2): 441–8. doi:10.1016/j.jaci.2006.09.035. PMID 17125820.
- ↑ Kaliner M, Shelhamer JH, Ottesen EA (1982). "Effects of infused histamine: correlation of plasma histamine levels and symptoms". J Allergy Clin Immunol. 69 (3): 283–9. doi:10.1016/s0091-6749(82)80005-5. PMID 6120967.
- ↑ Luster AD (1998). "Chemokines--chemotactic cytokines that mediate inflammation". N Engl J Med. 338 (7): 436–45. doi:10.1056/NEJM199802123380706. PMID 9459648.
- ↑ 21.0 21.1 Patel OP, Giorno RC, Dibbern DA, Andrews KY, Durairaj S, Dreskin SC (2015). "Gene expression profiles in chronic idiopathic (spontaneous) urticaria". Allergy Rhinol (Providence). 6 (2): 101–10. doi:10.2500/ar.2015.6.0124. PMC 4541630. PMID 26302730.
- ↑ 22.0 22.1 Losol P, Yoo HS, Park HS (2014). "Molecular genetic mechanisms of chronic urticaria". Allergy Asthma Immunol Res. 6 (1): 13–21. doi:10.4168/aair.2014.6.1.13. PMC 3881394. PMID 24404388.
- ↑ Bracken SJ, Abraham S, MacLeod AS (2019). "Autoimmune Theories of Chronic Spontaneous Urticaria". Front Immunol. 10: 627. doi:10.3389/fimmu.2019.00627. PMC 6450064. PMID 30984191.
- ↑ Kaplan AP (2017). "Chronic Spontaneous Urticaria: Pathogenesis and Treatment Considerations". Allergy Asthma Immunol Res. 9 (6): 477–482. doi:10.4168/aair.2017.9.6.477. PMC 5603475. PMID 28913986.
- ↑ Leznoff A, Sussman GL (1989). "Syndrome of idiopathic chronic urticaria and angioedema with thyroid autoimmunity: a study of 90 patients". J Allergy Clin Immunol. 84 (1): 66–71. doi:10.1016/0091-6749(89)90180-2. PMID 2754146.
- ↑ Sugiyama A, Nishie H, Takeuchi S, Yoshinari M, Furue M (2015). "Hashimoto's disease is a frequent comorbidity and an exacerbating factor of chronic spontaneous urticaria". Allergol Immunopathol (Madr). 43 (3): 249–53. doi:10.1016/j.aller.2014.02.007. PMID 25088672.
- ↑ Confino-Cohen R, Chodick G, Shalev V, Leshno M, Kimhi O, Goldberg A (2012). "Chronic urticaria and autoimmunity: associations found in a large population study". J Allergy Clin Immunol. 129 (5): 1307–13. doi:10.1016/j.jaci.2012.01.043. PMID 22336078.
- ↑ Simons FE (2001). "Prevention of acute urticaria in young children with atopic dermatitis". J Allergy Clin Immunol. 107 (4): 703–6. doi:10.1067/mai.2001.113866. PMID 11295661.
- ↑ Ye YM, Jin HJ, Hwang EK, Nam YH, Kim JH, Shin YS; et al. (2013). "Co-existence of chronic urticaria and metabolic syndrome: clinical implications". Acta Derm Venereol. 93 (2): 156–60. doi:10.2340/00015555-1443. PMID 22948845.
- ↑ Kay AB, Ying S, Ardelean E, Mlynek A, Kita H, Clark P; et al. (2014). "Elevations in vascular markers and eosinophils in chronic spontaneous urticarial weals with low-level persistence in uninvolved skin". Br J Dermatol. 171 (3): 505–11. doi:10.1111/bjd.12991. PMC 4282040. PMID 24665899.